1. Field of the Invention
The present invention is an improved process for preparing 7-halo-7-deoxylincomycins, including clindamycin, and pharmaceutically acceptable forms thereof from lincomycin and analogs thereof. Clindamycin is a well known antibiotic that has pharmacologically useful properties.
2. Prior Art
Processes for preparing 7-halo-7-deoxylincomycins are known. U.S. Pat. Nos. 3,435,025, 3,496,163 and 3,509,127 disclose a process in which the 7-hydroxyl group of lincomycin and analogous compounds are replaced with a halogen group by reacting said compounds with a Rydon reagent and heating the resulting product. The use of thionyl chloride to convert lincomycin and analogous compounds to 7-chloro-7-deoxy compounds is described in U.S. Pat. Nos. 3,496,163, 3,509,127 and 3,574,186. A process for preparing 7-halo-7-deoxylincomycin by the use of a sulfite-protected lincomycin and Rydon reagents is described in U.S. Pat. No. 3,714,141.
The use of a Vilsmeier reagent to substitute a halo atom for a hydroxyl group has been described. Eilingsfeld et al, Angew. Chem. 72, 836 (1960) and Eilingsfeld et al, Chem. Ber. 96 2671 (1963). Evans et al, JOC 33, 1074 (1968) discloses on page 1075 that while a Vilsmeier reagent prepared from methanesulfonyl chloride and dimethylformamide was successfully used to replace a primary hydroxyl group, it was not in attempts to replace a secondary hydroxyl group.
The structure of the adduct formed between dimethylformamide and thionyl chloride from which sulfur dioxide has not been removed has been investigated by Ferre et al, Tet. Lett. 2161 (1969) and the conditions for converting the dimethylformamide thionyl chloride adduct to the corresponding amide chloride has been described; Kikagawa et al, Chem. Pharm, Bull. 19, 2629 (1971). Bosshard et al, Helv. Chim. Acta. 42, 1653 (1959) discloses the use of dimethyl formamide as a catalyst in the conversion of carboxylic acids to acid chlorides.
Hepburn et al, J. Chem. Soc. Perkin I, 754 (1976) and Hepburn et al, Chem. & Ind. 664 (1974) describes the use of amide chlorides obtained from Vilsmeier reagents to replace hydroxyl groups by chlorine or bromine groups. However, the hydroxyl containing compounds were relatively simple alcohols and did not approach the complexity of the lincomycin molecule.
The use of a mixture of mesyl chloride and N,N-dimethylformamide to replace primary groups of hexopyranosides by chlorine is described by Edwards et al, Tetrahedron Letters, 2369 (1973).
The halogenation of nucleosides by amide chlorides is described by Dobs et al, Tetrahedron Letters, 165 (1969).
While the prior art describes the use of both Vilsmeier reagents and amide chlorides obtained therefrom in reactions similar to that of the process of this instant invention, the prior art is confusing at best. This is particularly true with respect to whether or not it is preferred to use the Vilsmeier reagent or to remove sulfur dioxide from it and use the resulting amide chloride.
Applicant has found that the use of the amide chloride rather than the Vilsmeier reagents to convert lincomycin type compounds to 7-halo-7-deoxylincomycin type compounds provides increased yields and products of improved quality.